Friday, August 28, 2009

What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results
Items 1 -6 of 6

1: PLoS One. 2009 Aug 27;4(8):e6805.

Glyoxalase I gene deletion mutants of Leishmania donovani exhibit reduced methylglyoxal detoxification.

Chauhan SC, Madhubala R.

School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

BACKGROUND: Glyoxalase I is a metalloenzyme of the glyoxalase pathway that plays a central role in eliminating the toxic metabolite methyglyoxal. The protozoan parasite Leishmania donovani possesses a unique trypanothione dependent glyoxalase system. PRINCIPAL FINDINGS: Analysis of the L. donovani GLOI sequence predicted a mitochondrial targeting sequence, suggesting that the enzyme is likely to be targeted to the mitochondria. In order to determine definitively the intracellular localization of GLOI in L. donovani, a full-length GLOI gene was fused to green fluorescent protein (GFP) gene to generate a chimeric construct. Confocal microscopy of L. donovani promastigotes carrying this chimeric construct and immunofluorescence microscopy using anti-GLOI antibodies demonstrated that GLOI is localized in the kinetoplast of the parasite apart from the cytosol. To study the physiological role of GLOI in Leishmania, we first created promastigote mutants heterozygous for GLOI by targeted gene replacement using either hygromycin or neomycin phosphotransferases as selectable markers. Heterozygous mutants of L. donovani display a slower growth rate, have lower glyoxalase I activity and have reduced ability to detoxify methylglyoxal in comparison to the wild-type parasites. Complementation of the heterozygous mutant with an episomal GLOI construct showed the restoration of heterozygous mutant phenotype nearly fully to that of the wild-type. Null mutants were obtained only after GLOI was expressed from an episome in heterozygous mutants. CONCLUSIONS: We for the first time report localization of GLOI in L. donovani in the kinetoplast. To study the physiological role of GLOI in Leishmania, we have generated GLOI attenuated strains by targeted gene replacement and report that GLOI is likely to be an important gene since GLOI mutants in L. donovani showed altered phenotype. The present data supports that the GLOI plays an essential role in the survival of this pathogenic organism and that inhibition of the enzyme potentiates the toxicity of methylglyoxal.

PMID: 19710909 [PubMed - in process]

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2: Curr Opin Clin Nutr Metab Care. 2009 Aug 25. [Epub ahead of print]

Zinc: role in immunity, oxidative stress and chronic inflammation.

Prasad AS.

Department of Internal Medicine, Division of Hematology/Oncology, Wayne State University, School of Medicine, Detroit, Michigan, USA.

PURPOSE OF REVIEW: Zinc is essential for multiple cellular functions including immunity. Many investigators have used zinc supplementation in an attempt to affect the outcome of various diseases. These efforts were aimed at either supporting immunity by zinc administration or correcting the zinc dependent immune functions in zinc deficient individuals. RECENT FINDINGS: In this review, recent findings of zinc supplementation in various diseases have been presented. Beneficial therapeutic response of zinc supplementation has been observed in the diarrhea of children, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory tract infection, common cold, and leishmaniasis. Zinc supplementation was effective in decreasing incidences of infections in the elderly, in patients with sickle cell disease (SCD) and decreasing incidences of respiratory tract infections in children. Zinc supplementation has prevented blindness in 25% of the elderly individuals with dry type of AMD. Zinc supplementation was effective in decreasing oxidative stress and generation of inflammatory cytokines such as TNF-alpha and IL-1beta in elderly individuals and patients with SCD. SUMMARY: Zinc supplementation has been successfully used as a therapeutic and preventive agent for many conditions. Zinc functions as an intracellular signal molecule for immune cells.

PMID: 19710611 [PubMed - as supplied by publisher]

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3: Bioorg Med Chem. 2009 Aug 12. [Epub ahead of print]

Novel 2H-isoquinolin-3-ones as antiplasmodial falcipain-2 inhibitors.

Micale N, Ettari R, Schirmeister T, Evers A, Gelhaus C, Leippe M, Zappalà M, Grasso S.

Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata 98168, Messina, Italy.

A series of 1-aryl-6,7-disubstituted-2H-isoquinolin-3-ones (2-10) was synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2, as well as against cultured P. falciparum strain FCBR parasites. All compounds displayed inhibitory activity against recombinant falcipain-2 and against in vitro cultured intraerythrocytic P. falciparum, with the exception of 9. The new compounds exhibited no selectivity against human cysteine proteases such as cathepsins B and L. The inhibitory activity of the synthesized compounds was also evaluated against another protozoal cysteine protease, namely rhodesain of Trypanosoma brucei rhodesiense.

PMID: 19709887 [PubMed - as supplied by publisher]

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4: Trop Med Int Health. 2009 Aug 25. [Epub ahead of print]

Species diversity of Leishmania (Viannia) parasites circulating in an endemic area for cutaneous leishmaniasis located in the Atlantic rainforest region of northeastern Brazil.

Brito ME, Andrade MS, Mendonça MG, Silva CJ, Almeida EL, Lima BS, Félix SM, Abath FG, da Graça GC, Porrozzi R, Ishikawa EA, Shaw JJ, Cupolillo E, Brandão-Filho SP.

Departamento de Imunologia, Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, Brazil.

Summary Objectives To identify the aetiological agents of cutaneous leishmaniasis and to investigate the genetic polymorphism of Leishmania (Viannia) parasites circulating in an area with endemic cutaneous leishmaniasis (CL) in the Atlantic rainforest region of northeastern Brazil. Methods Leishmania spp. isolates came from three sources: (i) patients diagnosed clinically and parasitologically with CL based on primary lesions, secondary lesions, clinical recidiva, mucocutaneous leishmaniasis and scars; (ii) sentinel hamsters, sylvatic or synanthropic small rodents; and (iii) the sand fly species Lutzomyia whitmani. Isolates were characterised using monoclonal antibodies, multilocus enzyme electrophoresis (MLEE) and polymerase chain reaction-restriction fragment length polymorphism of the internal transcribed spacer region rDNA locus. Results Seventy-seven isolates were obtained and characterised. All isolates were identified as Leishmania (Viannia) braziliensis serodeme 1 based on reactivity to monoclonal antibodies. MLEE identified 10 zymodemes circulating in the study region. Most isolates were classified as zymodemes closely related to L. (V.) braziliensis, but five isolates were classified as Leishmania (Viannia) shawi. All but three of the identified zymodemes have so far been observed only in the study region. Enzootic transmission and multiclonal infection were observed. Conclusions Our results confirm that transmission cycle complexity and the co-existence of two or more species in the same area can affect the level of genetic polymorphism in a natural Leishmania population. Although it is not possible to make inferences as to the modes of genetic exchange, one can speculate that some of the zymodemes specific to the region are hybrids of L. (V.) braziliensis and L. (V.) shawi.

PMID: 19708899 [PubMed - as supplied by publisher]

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5: Expert Opin Emerg Drugs. 2009 Sep;14(3):395-410.

Developments in the treatment of visceral leishmaniasis.

den Boer ML, Alvar J, Davidson RN, Ritmeijer K, Balasegaram M.

23A Oval Road, NW1 7EA London, UK. margrietdenboer@gmail.com

BACKGROUND: Visceral leishmaniasis (VL) is one of the most neglected parasitic diseases causing large scale mortality and morbidity among the poorest of the poor in the Indian subcontinent and Africa. OBJECTIVE: This review aims to describe the potential and the (lack of) current impact of newly developed treatments on the control of VL. It describes how the problem of an empty research pipeline is addressed, and discusses the emerging threat of incurable HIV/VL coinfection. METHODS: The literature was searched for drugs used in VL. CONCLUSION: Research and development of VL drugs has received a financial boost but no new drugs are expected in the next 5 years. Only three new and highly effective treatments have been licensed in the past 10 years. These remain, however, largely inaccessible as VL control programs in the developing world are lacking. This is deserving of immediate and urgent attention, especially in the context of the rapidly expanding HIV/VL coinfection.

PMID: 19708817 [PubMed - in process]

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6: Braz J Med Biol Res. 2009 Mar;42(3):220-3.Click here to read LinkOut

Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

Rodrigues MM, Alencar BC, Claser C, Tzelepis F.

Centro Interdisciplinar de Terapia Gênica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.

Intense immune responses are observed during human or experimental infection with the digenetic protozoan parasite Trypanosoma cruzi. The reasons why such immune responses are unable to completely eliminate the parasites are unknown. The survival of the parasite leads to a parasite-host equilibrium found during the chronic phase of chagasic infection in most individuals. Parasite persistence is recognized as the most likely cause of the chagasic chronic pathologies. Therefore, a key question in Chagas' disease is to understand how this equilibrium is established and maintained for a long period. Understanding the basis for this equilibrium may lead to new approaches to interventions that could help millions of individuals at risk for infection or who are already infected with T. cruzi. Here, we propose that the phenomenon of immunodominance may be significant in terms of regulating the host-parasite equilibrium observed in Chagas' disease. T. cruzi infection restricts the repertoire of specific T cells generating, in some cases, an intense immunodominant phenotype and in others causing a dramatic interference in the response to distinct epitopes. This immune response is sufficiently strong to maintain the host alive during the acute phase carrying them to the chronic phase where transmission usually occurs. At the same time, immunodominance interferes with the development of a higher and broader immune response that could be able to completely eliminate the parasite. Based on this, we discuss how we can interfere with or take advantage of immunodominance in order to provide an immunotherapeutic alternative for chagasic individuals.

PMID: 19287899 [PubMed - indexed for MEDLINE]

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